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  Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 4  |  Page : 442-446
 

Alarming prevalence of community-acquired multidrug-resistant organisms colonization in children with cancer and implications for therapy: A prospective study


1 Department of Paediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Medical and Pediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Microbiology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication1-Feb-2016

Correspondence Address:
B Arora
Department of Paediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.175310

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 » Abstract 

Background: Infection or colonization with multidrug-resistant organisms (MDRO) is associated with high mortality and morbidity. Knowledge of MDRO colonization may help in planning empirical antibiotic approach in neutropenic patients, which is known to improve patient outcomes. While routine cultures are positive and may help direct antibiotic therapy in only up to 15% neutropenic patients, surveillance cultures are positive in more than 90% of cancer patients. Aims: To assess the rate of MDRO carrier status at presentation and rate of conversion to MDRO during the treatment. Materials And Methods: Rectal swabs of all the outpatients presenting to pediatric oncology unit were sent within 7 days from date of registration from January 2014 to December 2014. Furthermore, stool cultures/rectal swabs of all patients who got directly admitted to the pediatric ward at presentation were sent within 24 h. Repeat rectal swabs were sent again for patients from this cohort when they got readmitted to the ward at least 15 days after last discharge or when clinically indicated. Results: Baseline surveillance rectal swabs were sent for 618 patients, which included 528 children with hematological malignancies and 90 children with solid tumors. Forty-five (7.3%) showed no growth. Of the remaining 573, 197 (34.4%) patients were colonized by two organisms and 30 (5.2%) by three organisms. Three hundred and thirty-four (58.4%) showed extended spectrum beta-lactamase (ESBL) Enterobacteriaceae, of which 165 (49.5%) were ESBL sensitive to beta-lactam with beta-lactamase inhibitors combinations and 169 (50.5%) were resistant to combinations. One hundred and sixteen (20.2%) were carbapenem-resistant Enterobacteriaceae (CRE) and 65 (11.4%) had vancomycin-resistant enterococci in baseline cultures. Only 63 (21%) patients were colonized by a sensitive organism in their baseline surveillance cultures. Morbidity (Intensive Care Unit stay) and mortality was higher in patients colonized by MDR organisms. There was a significant correlation between the place of residence and CRE colonization status with the highest rate (60%) of CRE colonization observed in children from East India. The repeat cultures showed the further conversion of sensitive isolates to MDRO in 80% of these children, of which 40% each converted from non-ESBL and non-CRE to ESBL and CRE, respectively. Conclusion: This is the first study illustrating the alarming high prevalence of community-acquired MDRO colonization, especially CRE, which has grave implications for therapy for children with cancer potentially compromising delivery of aggressive chemotherapy and affecting outcomes. This incidence further increases during the course of treatment. Knowing the baseline colonization also guides us for the planning of chemotherapy as well as antibiotic approach and infection control strategies. Local antibiotics stewardship including education of the healthcare workers as well as national level interventions to prevent antibiotic misuse in the community is critical to minimize this problem.


Keywords: Hematolymphoid, malignancy, oncology, pediatric, rectal swab, surveillance


How to cite this article:
Thacker N, Pereira N, Banavali S, Narula G, Vora T, Chinnaswamy G, Prasad M, Kelkar R, Biswas S, Arora B. Alarming prevalence of community-acquired multidrug-resistant organisms colonization in children with cancer and implications for therapy: A prospective study. Indian J Cancer 2014;51:442-6

How to cite this URL:
Thacker N, Pereira N, Banavali S, Narula G, Vora T, Chinnaswamy G, Prasad M, Kelkar R, Biswas S, Arora B. Alarming prevalence of community-acquired multidrug-resistant organisms colonization in children with cancer and implications for therapy: A prospective study. Indian J Cancer [serial online] 2014 [cited 2018 Oct 17];51:442-6. Available from: http://www.indianjcancer.com/text.asp?2014/51/4/442/175310



 » Introduction Top


Improvement in supportive care strategies has played a major role in making the treatment of childhood cancers a success story. Delivery of highly myelosuppressive chemotherapy regimens has been made possible by prompt handling of the infective complications with empirical broad-spectrum antibiotics. The recent increase in the incidence of multidrug-resistant organisms (MDRO) has made the choice of empirical antibiotics difficult and limited. Infection with MDRO is associated with high mortality, jeopardizing our ability to deliver intensive chemotherapy, necessitating appropriate infection prevention and control (IPC) measures and antibiotic stewardship.

Patient colonized by MDRO are not only at high risk of infectious death but are also a threat to other patients, if not identified early.[1] Up to 80% of patients colonized by MDRO are culture-negative by routine clinical cultures in nonstool sites and hence missed.[2] Active surveillance cultures allow early identification of MDRO carriers, for timely implementation of contact precautions (CP) to limit person-to-person spread.[1],[3] A de-escalation antibiotic approach, based on MDRO stool carrier status, has been recommended in high-risk groups recently.[4],[5] Rectal surveillance cultures are most appropriate as Enterobacteriaceae are routine colonizers of the gastrointestinal tract, with the potential of gut-translocation causing blood-stream infections during the periods of immunosuppression.[6],[7]

Having knowledge of surveillance cultures upfront would help us know the community-acquiredMDRO (CA-MDRO) carrier rate and guide in IPC strategy in an oncology unit, as well as in planning antibiotic policy and chemotherapy. Hence, the primary objective of this study was to assess the rate of CA-MDRO carrier status at presentation and rate of conversion to MDRO during the treatment at our center.


 » Materials and Methods Top


This was a prospective observational study conducted in Pediatric Oncology Department of Tata Memorial Hospital, which is a cancer referral center, catering to patients from all over India.

All newly diagnosed children with cancer, who had surveillance rectal swabs/stool cultures sent within 7 days of registration either from outpatient or inpatient unit (within 24 hrs), were enrolled for the study. Rectal swabs were collected in an out-patient clinic, and stool cultures were sent for admitted patients as part of active surveillance. Data were collected for a period of 12 months from January to December 2014. Repeat rectal swabs/stool cultures were sent for patients from this cohort when they got readmitted; not before 15 days from last discharge or when clinically indicated.

The bacteria from these samples were identified by the routine biochemical reactions. The antimicrobial sensitivity pattern of these organisms was determined by the Kirby Bauer's disc diffusion method. Choice of antibiotic disks used was determined by Clinical and Laboratory Standards Institute (CLSI) guidelines. A limited antibiotic panel was used focused at identifying extended spectrum beta-lactamase (ESBL) producers, carbapenem-resistant Enterobactericeae (CRE) and vancomycin-resistant enterococci organisms. ESBL production was confirmed by CLSI recommendations using cephalosporin–clavulanate combination disks. A difference of ≥5 mm between zone diameter of either of the cephalosporin disks and their respective cephalosporin–clavulanate disk was taken to be phenotypic confirmation of ESBL production. We used cefotaxime (30 μg), ceftazidime (30 μg), and ceftazidime/clavulanic acid (30 μg/10 μg) disks for ESBL determination. Carbapenem resistance was reported as per the CLSI guidelines. Vancomycin resistance was confirmed by minimal inhibitory concentrations with the "E" test. In an event when more than one organism with differing sensitivity profile was isolated from the culture, the worse sensitivity pattern was taken into account for analysis. The epidemiology of baseline stool carrier status and its sensitivity was analyzed.


 » Results Top


A total of 618 baseline surveillance rectal swabs/stool cultures were sent from pediatric oncology services during the study period. The study group consisted of 528 children with hematological malignancies and 90 with solid tumors.

Of the baseline surveillance cultures sent, 45 (7.3%) did not show any significant growth. From 573 positive cultures, 376 (65.6%) showed growth of the single organism, 197 (34.4%) patients were colonized by two organisms and 30 (5.3%) by three organisms.

Only 120 (21%) of children were carrying organisms that were pan-sensitive at presentation [Figure 1]. More than half of the ESBL organisms were resistant to the beta-lactam (cephalosporin) with beta-lactamase inhibitor combination.
Figure 1: Common bacterial groups based on sensitivity of baseline surveillance cultures

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Five hundred and eight (88.6%) cultures showed growth of Escherichia coli and 227 (39.6%) isolates grew Klebsiella pneumoniae. E. coli was the only growth in 446 patients, K. pneumoniae sole growth in 62 patients and both were grown in 165 patients. The sensitivity of these Enterobacteriaceae is illustrated in [Figure 2] with K. pneumoniae having a higher proportion of ESBL producers. Contemporary data from blood cultures showed 42% of E. coli and 35% of K. pneumoniae to be ESBL producers. While 34% and 48% of E. coli and K. pneumoniae isolates were carbapenem-resistant.
Figure 2: Baseline sensitivity pattern of common Enterobacteriaceae

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There was no difference in sensitivity of colonizers with respect to gender and category. As compared to hematological malignancies, patients with solid tumors had a higher proportion of sensitive colonizers (19% vs. 29%) and a lower proportion of ESBL organisms (60% vs. 49%). Alarmingly, children, who died of infections, had a much higher proportion of ESBL (70% vs. 58%) and CRE (26% vs. 20%) carrier rates, and a low-rate of sensitive colonization (4.3%). A similar trend was observed in patients requiring Intensive Care Unit (ICU) admission as shown in [Figure 3]. There was a significant difference in sensitivity of colonizers by place of residence [Figure 4]. Children from eastern states accounted for 60% of all the CRE colonizers.
Figure 3: Sensitivity pattern with various parameters

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Figure 4: Colonization pattern and place of residence

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Repeat cultures were obtained for 251 patients. Only 7/35 (20%) continued to have sensitive organisms at follow-up. Of the remaining non-ESBL carriers at baseline, 22/56 (39.3%) converted to ESBL carrier status. Similarly, 39.3% (66/168) of non-CRE carriers got converted to CRE carriers at follow-up.


 » Discussion Top


Infections are a major cause of morbidity and mortality in children with cancers, especially during periods of neutropenia. Management of febrile neutropenia has become an even bigger challenge with increasing infections by MDRO. The source of infection in immunocompromised children is often endogenous, with most MDRO organisms routinely colonizing their skin and mucosal surfaces, causing infections when physical and/or immunological defenses of the host are breached by chemotherapy and/or disease.[7]

This is the first study demonstrating the alarming high prevalence of colonization by CA-MDRO (61.5%), especially CRE (20.2%), in Indian children with cancer. MDRO colonization further gets amplified after repeated antibiotic usage and cross infections in the oncology unit with 80% of the sensitive organisms acquiring resistance, and 40% of non-ESBL and non-CRE converting to ESBL and CRE, respectively.

This alarming prevalence of MDRO in the community is multifactorial in origin. While antibiotic misuse in humans is among the most important risk factors, equally important is overuse of antibiotics in agriculture and animals which exceed human use. In 2009, more than 3 million kg of antibiotics were administered to humans, and a massive 13 billion kg of antibiotics were administered to animals to promote the growth of livestock in the USA.[8] Studies from many countries including India showing a high prevalence of drug-resistant isolates in cow dung further strengthens this theory.[9],[10],[11] Use of antibiotics in the household products such as antibacterial soaps or gels as well as triclosan in plastics is also rising and is a cause for concern.[12]

The place of residence was a strong predictor of colonization by MDRO in the present study, with children from eastern states accounting for 60% of CRE colonization. Multiple factors such as high population density, antibiotic prescribing policies, and contamination of water source by farm and hospital effluents could possibly explain this phenomenon.[13],[14]

The potential impact of contaminated water sources on the prevalence of MDRO in the community is illustrated by reports of water in Ganga and Yamuna in India showing growth of MDR bacteria, which forms a major source of drinking water in Northern and Eastern States.[15],[16] A recent study has recently demonstrated NDM-1 β-lactamase-producing bacteria in tap water and sewage samples in New Delhi, India.[17] This, potentially, leads to widespread colonization and community spread of MDRO, further complicated by poor sanitation, leading to soil and water contamination by both humans and animals, forming a vicious cycle. Further, studies have shown travel to India as a significant risk factor for colonization by MDRO.[18],[19]

There is a paucity of data on surveillance cultures from India, with three community-based studies from East, South and Central India showing 24–38% prevalence of MDRO isolates in surveillance stools cultures from children. Resistance to carbapenems in these community studies ranged from 0% to 12%.[11],[20],[21] The lower MDRO rates in these studies are due to the community sampling versus hospital-based sampling in our study. Furthermore, these studies studied only E. coli isolates in healthy children. A sole hospital based study from North India demonstrated 10% CRE isolates in 242 patients attending an out-patient department screened by stool culture.[22] The prevalence of MDRO especially CRE colonization in the present study is higher than community-based studies in healthy children from other developing countries in South America, North America, and Europe.[23],[24],[25],[26] European EARS-Net 2013 data showed 85–100% of E. coli and K. pneumoniae to be ESBL. While <0.5% E. coli isolates were CRE, 0–59.4% of K. pneumoniae wereCREvarying with region. [27] ESPAUR-2013 data published from the UK estimated the national rate of ESBL E. coli and K. pneumoniae at 10.9% and 11.4%. While the CRE rate for E. coli and K. pneumoniae were low at <1% and 3.8%, respectively.[28] CDC, USA has recently estimated CRE in K. pneumoniae and E. coli at 11% and 2%, respectively together accounting for 600 deaths annually.[3] The majority of patients in our study had hospital stay and antibiotic usage before presentation to our center, which adds to a higher rate of MDR and CRE colonization as compared to the community studies in India and Abroad. Lack of molecular typing of isolates and inadequate details of antibiotic usage prior to presentation at our center are major limitations of our study.

Overall, there has been an increase in the prevalence of MDRO in the last decade globally, which is much more in India compared to Western populations.[27],[28],[29] A large medical community, more than 20,000 hospitals, enormous population, availability of over the counter antibiotics and lack of a national antibiotic stewardship program has contributed to antibiotic resistance in India. Higher morbidity (ICU stay) and mortality in children colonized with MDRO, especially CRE as demonstrated by the present study is concerning. A correlation with frequency and sensitivity contemporary blood culture isolates shows a similar pattern of organisms and high rates of MDRO confirming the endogenous source of these bugs. This has implications on therapy, not only on the choice of empirical antibiotics but also in the modification of aggressive chemotherapy delivery in MDRO colonized children with cancer. The knowledge gained from this study has given us many critical insights; (1) plan IPC strategies including isolation and CP to limit further spread of this organism in the oncology unit, (2) formulation of antibiotic policy including adoption of a de-escalation approach for febrile neutropenia as incidence of MDRO colonization in our units is more than 20% (3) judicious planning of treatment intensity in view of higher morbidity and mortality in this MDRO colonized children.

The challenge of increasing antibiotic resistance in community, which gets further worse in hospitals, is very complex requiring a systematic approach not only at institute level but also at national and international level which can be based on recent CDC recommendations which include (1) preventing infections from occurring and preventing resistant bacteria from spreading, (2) tracking resistant bacteria, (3) improving the use of antibiotics, and (4) promoting the development of new antibiotics and new diagnostic tests for resistant bacteria. Further, novel successful therapies like fecal duodenal infusion for the eradication of resistant Clostridium difficile infection may require similar approaches before intensive chemotherapy in children with cancer.[30] Furthermore, therapies that are immune-based or target host inflammation are the need of the hour.[8] Though we have won many a battle in the past against the microbes, we will lose the future wars if we do not act now.

 
 » References Top

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[PUBMED]  Medknow Journal  
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Kumar R, Indira K, Rizvi A, Rizvi T, Jeyaseelan L. Antibiotic prescribing practices in primary and secondary health care facilities in Uttar Pradesh, India. J Clin Pharm Ther 2008;33:625-34.  Back to cited text no. 14
    
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Tängdén T, Cars O, Melhus A, Löwdin E. Foreign travel is a major risk factor for colonization with Escherichia coli producing CTX-M-type extended-spectrum beta-lactamases: A prospective study with Swedish volunteers. Antimicrob Agents Chemother 2010;54:3564-8.  Back to cited text no. 18
    
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Yaita K, Aoki K, Suzuki T, Nakaharai K, Yoshimura Y, Harada S, et al. Epidemiology of extended-spectrum ß-lactamase producing Escherichia coli in the stools of returning Japanese travelers, and the risk factors for colonization. PLoS One 2014;9:e98000.  Back to cited text no. 19
    
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Seidman JC, Anitha KP, Kanungo R, Bourgeois AL, Coles CL. Risk factors for antibiotic-resistant E. coli in children in a rural area. Epidemiol Infect 2009;137:879-88.  Back to cited text no. 20
    
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Shakya P, Barrett P, Diwan V, Marothi Y, Shah H, Chhari N, et al. Antibiotic resistance among Escherichia coli isolates from stool samples of children aged 3 to 14 years from Ujjain, India. BMC Infect Dis 2013;13:477.  Back to cited text no. 21
    
22.
Rai S, Das D, Niranjan DK, Singh NP, Kaur IR. Carriage prevalence of carbapenem-resistant Enterobacteriaceae in stool samples: A surveillance study. Australas Med J 2014;7:64-7.  Back to cited text no. 22
    
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29.
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30.
van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407-15.  Back to cited text no. 30
    


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